The mu opiate receptor (OR) has been identified as the principal brain receptor site best correlated with the rewarding and euphoric properties of opiate drugs. Euphoric responses to rapid administration of morphine and heroin can be much more prominent than those that follow slower rates of administration. Receptor phosphorylation is thought to play a role in processes which may contribute to rate- sensitivity of opiate receptor responses, and possibly to tolerance to opiates. In this FY, investigators in this Branch have documented direct phosphorylation of the muOR, with distinct patterns driven by protein kinase C and by agonist occupancy of the receptor. They have also continued to assess the roles of specific receptor sequences in functional properties. Attention focused on the His 297 amino acid, at which replacements can confer agonist properties on mu antagonists such as naloxone. These studies are important for defining molecular features important for intrinsic activity and for patterns of heterologous and homologous desensitization of the principal opiate receptor subtype implicated in reward and in analgesia. They have used knockout/homologous recombination strategies to delete half- or all of the mu receptor expression in vivo, and identified surprising influences on baseline pain behaviors and influences of morphine, heroin, as well as agonists at delta and kappa receptors.